Viral Infections and Bovine Mastitis - A Review

Viral infections and bovine mastitis: a review

G.J. Wellenberga,*, W.H.M. van der Poelb, J.T. Van Oirschota

aDivision of Infectious Diseases and Food Chain Quality, Institute for Animal Science and Health (ID-Lelystad),

P.O. Box 65, 8200 AB Lelystad, The NetherlandsbMicrobiological Laboratory for Health Protection (MGB), National Institute of Public Health and

the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands

Received 16 November 2001; received in revised form 29 April 2002; accepted 5 May 2002

Abstract

This review deals with the role of viruses in the aetiology of bovine mastitis. Bovine herpesvirus 1,

bovine herpesvirus 4, foot-and-mouth disease virus, and parainfluenza 3 virus have been isolated

from milk from cows with clinical mastitis. Intramammary inoculations of bovine herpesvirus 1 or

parainfluenza 3 virus-induced clinical mastitis, while an intramammary inoculation of foot-and-

mouth disease virus resulted in necrosis of the mammary gland. Subclinical mastitis has been induced

after a simultaneous intramammary and intranasal inoculation of lactating cows with bovine

herpesvirus 4. Bovine leukaemia virus has been detected in mammary tissue of cows with subclinical

mastitis, but whether this virus was able to induce bovine mastitis has not been reported.

Bovine herpesvirus 2, vaccinia, cowpox, pseudocowpox, vesicular stomatitis, foot-and-mouth

disease viruses, and bovine papillomaviruses can play an indirect role in the aetiology of bovine

mastitis. These viruses can induce teat lesions, for instance in the ductus papillaris, which result in a

reduction of the natural defence mechanisms of the udder and indirectly in bovine mastitis due to

bacterial pathogens. Bovine herpesvirus 1, bovine viral diarrhoea virus, bovine immunodeficiency

virus, and bovine leukaemia virus infections may play an indirect role in bovine mastitis, due to their

immunosuppressive properties. But, more research is warranted to underline their indirect role in

bovine mastitis.

We conclude that viral infections can play a direct or indirect role in the aetiology of bovine

mastitis; therefore, their importance in the aetiology of bovine mastitis and their economical impact

needs further attention.

# 2002 Elsevier Science B.V. All rights reserved.

Keywords: Cattle-viruses; Mastitis; Milk; Somatic cell count; Viruses

Veterinary Microbiology 88 (2002) 27–45

Abbreviations: BHV, bovine herpesvirus; BLV, bovine leukaemia virus; BVDV, bovine viral diarrhoea virus;

FMD, foot-and-mouth disease; SCC, somatic cell count* Corresponding author. Tel.: þ31-320-238219; fax: þ31-320-238050.

E-mail address: [email protected] (G.J. Wellenberg).

0378-1135/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.

PII: S 0 3 7 8 - 1 1 3 5 ( 0 2 ) 0 0 0 9 8 - 6

1. Introduction

Bovine mastitis is a highly prevalent disease in dairy cattle, and one of the most

important diseases affecting the world’s dairy industry; it places a heavy economic burden

on milk producers all over the world (Miller and Dorn, 1990; Schakenraad and Dijkhuizen,

1990; Miller et al., 1993; Bennett et al., 1999). Worldwide, annual losses due to mastitis

have been estimated to be approximately 35 billion US dollar. In the US, the annual costs of

mastitis have been estimated to be 1.5–2.0 billion US dollar, while losses of milk

productions, due to subclinical mastitis, and higher cow replacements costs associated

with high somatic cell counts (SCCs) were estimated at 960 million US dollar (Wells et al.,

1998). Each case of clinical mastitis in the US and California costs approximately 107 and

200 US dollars, respectively (Miller et al., 1993). In Scottish dairy herds, facing high bulk-

tank SCC, the average annual costs of subclinical mastitis was 100 Pound Sterling/cow

(Yalcin et al., 1999), while in the UK and the Netherlands, the annual average revenue

losses were calculated to be 42–84 Pound Sterling/cow (Esslemont and Peeler, 1993) and

approximately 59 Euro/cow (Schakenraad and Dijkhuizen, 1990).

Mastitis is defined as an inflammatory reaction of the parenchyma of the mammary

gland that can be of an infectious, traumatic or toxic nature (International Dairy Federation,

1987). Mastitis is characterized by physical, chemical and usually bacteriological changes

in the milk and by pathological changes in the glandular udder tissue. The diagnosis of

mastitis is based on clinical signs, e.g. swelling of the udder, tender to the touch, fever, and

depression. In many cases a reduced milk production can be observed. Because of the large

number of subclinical mastitis cases, the diagnosis of mastitis can also depend on indirect

tests which in turn depends on, e.g. the leukocyte numbers in the milk (Radostits et al., 1994).

Bovine mastitis is generally considered to be of infectious nature leading to inflamma-

tion of one or more quarters of the mammary gland and it is often affecting not only the

individual animal but the whole herd or at least several animals within the herd. If left

untreated, the condition can lead to deterioration of animal welfare resulting in culling of

affected cows, or even death.

Mastitis-causing pathogens include bacteria and non-bacterial pathogens, like myco-

plasms, fungi, yeasts, and chlamydia (Watts, 1988; Radostits et al., 1994). These pathogens

infect the udder generally through the ductus papillaris, which is the only opening of the

udder to the outside world.

Despite intensive aetiological research, still around 20–35% of clinical cases of bovine

mastitis have an unknown aetiology (Miltenburg et al., 1996; Wedderkopp, 1997).

Miltenburg et al. (1996) found a 28% negative rate in 1045 cases of clinical mastitis,

and Wedderkopp (1997) did not note pathogens in 35% of 6809 milk quarters in 3783 cows

suffering from clinical mastitis. The percentage of culture-negative samples of both

clinical and subclinical mastitis cases in the Netherlands has recently been determined

to be approximately 25% (Barkema et al., 1998). An explanation for these high percentages

of culture-negative samples might be a low concentration of udder pathogens, e.g.

Escherichia coli. Other pathogens such as mycoplasma, yeasts and moulds are difficult

to cultivate. But these agents cannot be the explanation for all culture-negative milk

samples from mastitis cows, because these agents are no common udder pathogens

(Pfutzner, 1994; Wendt, 1994). Due to the high percentages of unknown causes of mastitis,

28 G.J. Wellenberg et al. / Veterinary Microbiology 88 (2002) 27–45

it is obvious to study the role of viruses in the aetiology of bovine mastitis. This in spite of

the fact that viruses are generally considered not to play an important role. Watts (1988),

e.g., identified 137 microbial species as causative agents of bovine mastitis, including

agents involved in its pathogenesis. However, viruses were not included.

The reasons for this negligence could be manifold. Historically, mastitis research has

concentrated on bacterial pathogens. In case of viral infections, signs of mastitis may not have

been recognised because other clinical signs were more prominent. Subclinical mastitis cases

are often not diagnosed and consequently their aetiology is not investigated. This may cause

an underestimation of virus infections involved in bovine subclinical mastitis. Another

reason might be that lactating cows are seldom used inviral pathogenesis studies. In, e.g. most

BHV1 pathogenesis studies, young calves are used due to economic aspects. A disadvantage

thereof is that it does not yield any indication as to whether BHV1 can be involved in the

aetiology of bovine mastitis. In addition, milk samples from mastitis cows are often not

properly collected, treated and stored for virological research, as this requires special care.

The laboratory diagnosis of viral mastitis is laborious and expensive. Diagnostic tools, e.g.

susceptible cells, for the detection of viruses are often not optimally used. These arguments

might explain why it is difficult to estimate the importance of viral infection on the aetiology

of bovine mastitis and their economical impact. It also explains the low number of viral

mastitis reports, and it may explain why the last brief review on viral infections of the bovine

mammary gland has been published 30 years ago (Afshar and Bannister, 1970). This review

paper aims to make an inventory of the updated evidence that demonstrate whether viral

infections are associated in a direct or indirect way with bovine mastitis (Table 1).

Table 1

Viral infections and their association with bovine mastitis

Virus Natural cases

(virus isolation)

Experimental reproduction Indirect by

teat lesions

Epidemiological

studiesIM routea Natural route

BHV1 þ þ Db

BHV4 þc þ (þ)b

FMD virus þ þ þ þPI3 virus þ þBLV (þ)d Db

BHV2 þCowpox virus (þ)e

Pseudocowpox virus (þ)b

Vesicular stomatitis virus (þ)e

Bovine papillomaviruses þBVDV þBIV Db

Rinderpest virus Db

Bovine enterovirus þa Intramammary.b Data are considered to be insufficient for clear association.c Virus isolation from cases and not from matched controls.d No virus isolated but viral particles detected by electron microscopy.e Probably low incidence.

G.J. Wellenberg et al. / Veterinary Microbiology 88 (2002) 27–45 29

2. Viral infections and bovine clinical mastitis

Bovine herpesvirus (BHV)1 (Gourlay et al., 1974; Roberts et al., 1974), BHV4

(Wellenberg et al., 2000), foot-and-mouth disease (FMD) virus (Burrows et al., 1971),

and parainfluenza 3 (PI3) virus (Kawakami et al., 1966a,b) have been detected in milk

from cows with clinical mastitis. However, the detection of virus in milk from cows with

mastitis obviously does not prove that these agents are the cause of mastitis, or that they are

involved in an indirect way.

2.1. BHV1

BHV1, a member of the Alphaherpesvirinae subfamily within the Herpesviridae family,

causes infectious bovine rhinotracheitis (IBR), infectious pustular vulvovaginitis (IPV) and

infectious pustular balanoposthitis. In 1974, BHV1 was isolated from a cow with mastitis

in the USA. Although, bacterial culture was negative and only BHV1 was isolated from the

milk, the evidence that the virus caused the mastitis was, at most, circumstantial as the milk

sample was collected 3 days after vaccination with a live IBR-vaccine (Roberts et al.,

1974). In France, BHV1 was isolated from milk samples from cows with mastitis in

combination with Mycoplasma agalactiae (Espinasse et al., 1974; Gourlay et al., 1974).

BHV1 was also isolated from one of the milk samples obtained from one out of 96 cows

with mastitis (Bilge, 1998). Besides the isolation of BHV1 in milk, the virus was also

isolated from vesicular lesions on the udder and on the teats of a cow. Thus, BHV1 was

associated with cutaneous lesions of the bovine udder, however, it was difficult to ascertain

whether the lesions were primarily caused by the BHV1 infection (Guy et al., 1984).

A possible role of BHV1 in the aetiology of bovine mastitis, without or in combination

with bovine viral diarrhoea virus (BVDV), was also suggested by Siegler et al. (1984), who

described a high incidence of mastitis cases in a number of herds with BHV1- and BVDV-

infected cows. Bacteriological examination of bovine milk samples in a number of herds

suffering from mastitis revealed no udder pathogens, while others suffered from mastitis

induced by e.g. staphylococci and streptococci. Immunisation of cows in the affected herds

with IBR/IPV vaccine, without or in combination with mucosal disease/BVD vaccine,

resulted in an effective control of their mastitis problems, including the herds suffering

from mastitis induced by, e.g. staphylococci and streptococci. Any clear evidence that

BHV1 or BVDV were involved in these mastitis cases was not presented, as no attempts

were made to isolate BHV1 or BVDV from milk of affected cows, and no data were

presented about unvaccinated control cows within the same herds.

BHV1 has been shown to replicate in the bovine mammary gland and to induce signs of

clinical mastitis after an intramammary inoculation (Greig and Bannister, 1965; Straub and

Kielwein, 1966; Corner et al., 1967). An intramammary inoculation of one young heifer

with a BHV1-IBR or a BHV1-IPV strain-induced swollen quarters, hard and tender to the

touch (Greig and Bannister, 1965). A strong reduction in milk yield was recorded, and milk

samples showed abnormal morphology, with clots and blood, after the intramammary

inoculation of cows with the BHV1-IBR strain. Virus was first isolated from infected

quarters on day 2 post-inoculation (pi) which continued up to days 10–15 pi. The virus

reached titres up to 106–107 TCID50/ml. No virus was detected in the milk from the two


uninoculated control quarters. Clinically, the experimental mastitis produced by the

BHV1-IBR strain was similar to that induced by the BHV1-IPV strain. Dilution series

further demonstrated that about 103 TCID50 BHV1/ml was required to produce infection of

the mammary gland by the intramammary route (Greig and Bannister, 1965). In another

study, an intramammary inoculation with BHV1-IPV resulted in clinical mastitis as

evidenced by an increase in body temperature, decreased appetite, painful and swollen

udders, and a strong reduction of the milk yield. It was possible to isolate the virus from the

milk of inoculated quarters until day 11 pi (Straub and Kielwein, 1966).

Experimental BHV1 infections of the mammary gland resulted in necrosis of the

alveolar epithelial layer, infiltration and accumulation of polymorphic and mononuclear

cells, and inclusion bodies in the nuclei of epithelial cells (Corner et al., 1967).

The above mentioned studies demonstrate that BHV1 has been isolated from natural

cases of mastitis and that the bovine udder is susceptible to BHV1. However, its impact on

bovine mastitis cases in general is unclear. In view of the ubiquitous character of this virus,

the number of reported mastitis cases in which BHV1 played a role is probably low. BHV1

was not isolated from milk of any of the 58 natural clinical mastitis cases from 10 herds

examined virologically by Wellenberg et al. (2000). BHV1 is probably not a major primary

udder pathogen.

2.2. BHV4

BHV4, a rhadinovirus and member of the Gammaherpesvirinae subfamily within the

Herpesviridae family, has been isolated from cows with various clinical signs, including

mammary pustular dermatitis (Reed et al., 1977), and chronic ulcerative mammary

dermatitis (Cavirani et al., 1990). Recently, BHV4 has been isolated from three milk

samples of 3 (5%) out of 58 cows with clinical mastitis, and not from the 58 matched

control cows. Two of the three cows from which BHV4 was isolated developed antibodies

against BHV4, while no increase in antibodies against BHV4 were detectable in the third

cow within 21 days. A possible role of BHV4 in bovine mastitis was further supported by

the fact that in 4 of the 10 herds examined there was an ongoing BHV4 infection at the same

time as mastitis occurred (Wellenberg et al., 2000). In a second case-control study, a part of

the gene coding for BHV4-glycoprotein B was detected by PCR (Wellenberg et al., 2001)

in milk samples from 2 (4%) out of 54 mastitis cows. From the same milk samples, BHV4

was isolated on bovine umbilical cord endothelial cells, a cell type highly susceptible to

bovine herpesviruses (Wellenberg et al., in press). A significant increase in BHV4 antibody

titres was detected in 1 of these 2 mastitis cows at the same time as mastitis occurred. No

BHV4 was detected in milk from their matched control cows by gB-PCR or virus isolation.

In both case-control studies, the presence of BHV4 was in most cases accompanied

by bacterial udder pathogens, e.g. Staphylococcus aureus and Streptococcus uberis. An

experimental study, performed to further investigate the role of BHV4 in bovine mastitis,

showed that a simultaneous intramammary and intranasal inoculation of lactating cows

with BHV4 did not result in clinical mastitis. However, subclinical mastitis was induced in

2 out of 4 inoculated lactating cows (Wellenberg et al., 2002). A significant increase of SCC

was recorded in milk from 50% of the BHV4 inoculated quarters on days 8, 9 and 11 pi,

compared to the non-inoculated quarters of the same cows (within-cow controls) and the


quarters of the mock-inoculated cows. Virus was isolated from milk samples of inoculated

quarters only; from day 1 to days 9–14 pi. A S. uberis infection appeared to trigger BHV4

replication in cows infected 2 weeks before with BHV4. BHV4 was isolated from the milk

from 2 out of 4 quarters after an intramammary S. uberis inoculation.

During an epidemiological study, a positive association between the presence of BHV4

antibodies in cows and the incidence of bovine mastitis caused by S. aureus was recorded

(Zadoks et al., 2001). This finding suggests that a previous BHV4 infection promotes the

development of mastitis especially caused by S. aureus. BHV4 has also been isolated from

the cellular fraction of milk samples from cows with antibodies against BHV4. Unfortu-

nately, no clinical data were reported on mastitis in these cows (Donofrio et al., 2000).

All above mentioned studies strongly suggest a role for BHV4 in bovine mastitis.

Although, BHV4 probably does not appear to play an important role as primary udder

pathogen in the aetiology of clinical mastitis, it may play a role in subclinical mastitis

cases, or in an indirect way. More research is warranted to establish a possible indirect role

of BHV4 infections in bovine mastitis, e.g. as a result of immunosuppression. The virus can

infect cells involved in the immune system, e.g. mononuclear blood cells (macrophages),

and recently, a possible role of BHV4 has been postulated by playing a role in damaging

vascular tissues (Lin et al., 2000). In addition, bovine endothelial cell cultures are highly

susceptible to BHV4.

2.3. FMD virus

FMD virus, a member of the Aphthovirus genus within the family of the Picornaviridae,

in general causes an infection whereby the virus is widespread through various tissues and

organs of the host. Although, a primary infection of the mammary gland is unlikely to be a

common occurrence in the pathogenesis of FMD, the virus can also replicate in the

secretory epithelial cells of the mammary gland. Many researchers have isolated FMD

virus from milk of FMD-affected cows (Burrows, 1968; Ray et al., 1989; Fuchs, 1994), and

also teat and udder lesions have been reported in FMD-affected cattle during an outbreak

with an Asia-1 serotype (Firoozi et al., 1974).

The results of experimental inoculations of the udder show that it is a highly susceptible

organ that is capable of producing large amounts of virus. Evidence for the replication of

FMD virus in the mammary glands, as a result of a systemic infection, was found in cattle

that were infected by (simulated field-type) contact exposure to FMD virus infected

animals (Blackwell et al., 1983). Infection of FMD virus by the oronasal route also resulted

in virus replication in secretory epithelial cells of the alveoli of the udder (Blackwell and

Yilma, 1981), and in progressive temporal necrosis in the alveoli. Clumps of necrotic

secretory epithelial cells and detached membrane-limited structures (cellular debris) were

observed within the alveolar lumen and in the milk (Blackwell et al., 1983). During

experimental infection, an increase of leukocytes was not recorded up to day 17 pi. This

means that FMD virus infections of the bovine udder result in necrosis of the alveolar

epithelial cells, but this occurs without a strong increase in leukocytes as observed for most

bacterial udder infections. So, FMD virus is not the cause of a viral clinical mastitis as such,

but secondary bacterial infections may result in clinical mastitis. The necrosis process is

probably responsible for the observed decrease in milk yield (Blackwell and Wool, 1986).


Replication of FMD virus in the mammary gland has also been reported after cows were

exposed to the virus either by aerosol, by a combination of intramammary-intravenous

inoculation (Blackwell and Yilma, 1981), or after an intramammary inoculation via the

ductus papillaris (Burrows et al., 1971). After intramammary inoculation, affected quarters

became swollen and tender to the touch. The milk showed abnormal morphology (with

clots), and a drop in the milk yield of approximately 60% was recorded. The FMD virus

multiplied rapidly and virus titers of >107 plaque forming units/ml were recorded within

8–32 h pi. Dissemination of the virus from the mammary gland was recorded by virus

isolation from milk within 4–24 h pi. The ability of FMD virus to persist in the mammary

tissue was confirmed by the intermittent recovery of the virus from cows up to day 51 pi,

which indicates virus multiplication in the udders of immune cows (Burrows et al., 1971).

Based on reports of natural mastitis cases and experimental infections, we may conclude

that the udder is a highly susceptible organ for FMD. Infection of the secretory epithelial

cells of the mammary gland will usually be the result of a systemic infection, because a

primary infection of the mammary gland by this virus is unlikely to be a common

occurrence. Mastitis associated with FMD virus is assumed to be due to secondary bacterial

infections.

2.4. PI3 virus

In 1966, PI3 virus, a member within the Paramyxoviridae family (order Mononegavir-

ales), was recovered from Japanese cattle with acute respiratory illness from nasal

secretions, and also from milk (Kawakami et al., 1966a). On one of the examined farms,

the virus was recovered from milk in 14 of 58 cows (24%). The cows from which PI3 virus

was recovered from the milk did not show signs of clinical mastitis, but an increased milk

SCC was recorded in many milk samples. PI3 virus was also isolated from quarter milk

from one cow of the same farm with typical aseptic mastitis.

An intramammary inoculation of PI3 virus resulted in respiratory signs and other signs,

e.g. fever, malaise, and losing condition, as observed in calves infected with the same PI3

virus by intravenous or intranasal inoculation. The affected udders developed swelling and

induration. The milk showed a color change, an increased pH and increased numbers of

glandular epithelial cells, neutrophils, lymphocytes and monocytes. Virus was excreted in

high titers (up to 107 TCID50/0.1 ml) in milk from inoculated quarters up to day 10 pi. The

histological examination revealed that the major change was an interstitial inflammation,

consistent of large lymphoid cells (Kawakami et al., 1966b). Both studies indicate that the

mammary gland is highly susceptible to PI3 virus, and that in naturally PI3 virus infected

cows udder infections may also occur. In some cases the infection may result in overt

clinical mastitis. These findings await confirmation.

3. Viral infections and bovine subclinical mastitis

A possible role of viruses in bovine subclinical mastitis has been suggested before

(Fuchs, 1994). Subclinical mastitis occurs frequently, and may lead to high economical

losses due to reduced milk yields, and to penalties because of too high bulk-tank SCCs.


Losses resulting from both clinical and subclinical mastitis may amount to 20% of the

potential production (Beck et al., 1992). In practice, subclinical mastitis cases are often not

detected rapidly, or may even not be recognized by the farmer.

3.1. Bovine leukaemia virus (BLV)

BLV belonging to the Deltaretrovirus genus and member of the family of Retroviridae

(Pringle, 1999), causes enzootic bovine leukosis. It preferentially infects lymphocytes of

the B-lineage in cattle. Recently, BLV particles have been detected by electron microscopy

around lymphocytes in the mammary tissue of BLV antibody positive cows affected by

subclinical mastitis (Yoshikawa et al., 1997). No macroscopical lesions were detected in

the mammary glands of the six cows examined, but histological lesions were found in some

lobules of the mammary gland, i.e. an infiltration of lymphocytes, plasma cells, and

neutrophils into alveoli and interlobular connective tissue. The alveoli also contained

numerous macrophages and desquamated alveolar lining cells. No information was

recorded about the milk SCC, the presence of bacterial udder pathogens or milk yields.

Consequently, whether this virus was the causative agent in this ‘‘subclinical’’ mastitis case

is unknown. No experimental studies have been reported to investigate whether BLV is able

to induce subclinical or clinical bovine mastitis. Such experiments are necessary to gain

more insight into the role of BLV in the aetiology of bovine mastitis.

4. Viral infections and their indirect role in bovine mastitis

Can viral infections play an indirect role in the pathogenesis of bovine mastitis? Damage

of teat and ductus papillaris (as natural barrier) and immunosuppression may lead to a

higher susceptibility for bacterial mastitis cases, and bacterial infections may run a more

severe course.

4.1. Teat lesions

Bovine herpes mammillitis virus (BHV2), vaccinia, cowpox, pseudocowpox, FMD

viruses, and to a lesser extent vesicular stomatitis virus can cause a local dermatitis, often

with ulcerations in the ductus papillaris, leading to secondary bacterial infections in the

sinus lactiferus and the corresponding mammary gland (Turner et al., 1976; Francis, 1984;

Scott and Holliman, 1984).

4.1.1. BHV2

Bovine mammillitis is an acute viral disease of cattle caused by BHV2 (Martin et al.,

1966), a virus of the genus Simplexvirus and member of the Alphaherpesvirinae subfamily

within the Herpesviridae family. BHV2 often infects young heifers and young cows at first

parity or in the first lactation period. The infection may be subclinical or relatively mild

(Turner et al., 1976; Letchworth and LaDue, 1982; Scott and Holliman, 1984), but it can

also be very severe causing extensive painful ulcerations on one or more teats and udders

(Scott and Holliman, 1984). Lesions can range from vesicles and ulcerations of large (up to


10 cm wide) areas of teat skin to single small (2–3 cm wide) plaques of oedema. Severe

BHV2 infections may also result in damage of the ductus papillaris. The functions of the

keratin in the ductus papillaris, with its fatty acids and proteins, and the macrophages,

lymphocytes and plasma cells in the ductus papillaris and the sinus lactiferus may be

impaired due to this BHV2 infection (Paape et al., 1985; Senft and Neudecker, 1991).

This may enhance the susceptibility of the mammary gland for bacterial mastitis (Martin

et al., 1969; Letchworth and LaDue, 1982; Scott and Holliman, 1984; Gourreau et al.,

1989).

BHV2 has also been isolated from milk from cows with ulcera on teats (Martin et al.,

1969), but leakage from these lesions was probably the cause of the presence of BHV2 in

the examined milk samples. Turner et al. (1976) recorded mastitis cases in cows with

BHV2 infection. These cows had ulcera in the ductus papillaris, and therefore its function

was impaired. Chronic mastitis was observed in cows with udder ulcera up to the ductus

papillaris. These reports suggest that BHV2 may induce mastitis due to damage of the

mechanical defence of the udder. Mastitis indirectly due to BHV2 infections (Letchworth

and LaDue, 1982; Scott and Holliman, 1984) mostly affect a few cows within a herd, but

also percentages of 22% have been recorded for BHV2 affected cows that developed

mastitis (Martin et al., 1969). Under experimental conditions, an intradermal and intra-

venous inoculation of a 30-month-old heifer with BHV2 resulted in several clinical signs,

e.g. mammillitis. However, in this study mastitis has not been recorded and the mammary

gland has not been examined for histopathological lesions (Tabbaa et al., 1987).

In conclusion, BHV2 infections can result in damage of the natural defence mechanisms

of the udder, which results in a higher susceptibility to bacterial mastitis. On the other hand,

BHV2 infections are more restricted within individual herds and its impact is less within

regions or countries. In addition, the number of published mastitis cases due to BHV2

infections was low within the last decade, and therefore, its role in bovine mastitis may not

be overestimated.

4.1.2. Vaccinia virus and cowpox virus

Infections with vaccinia virus and cowpox virus, both belonging to the genus Ortho-

poxvirus within the subfamily Chordopoxvirinae of the Poxviridae family, do not occur

anymore or are very rare, respectively (Mayr and Czerny, 1990). Clinical signs are

comparable to those described for BHV2 infections. As a result of teat lesions, mastitis

may occur in the same way as it occurs after a BHV2 infection. After an intramammary

inoculation with vaccinia virus, the virus that has been used for smallpox vaccination, an

inflammatory reaction in the bovine mammary gland was produced (Easterday et al.,

1959). The intramammary inoculation of the mammary glands via the ductus papillaris of

six cows with vaccinia virus (strain IHD) induced systemic signs, e.g. elevated body

temperatures, and udder swelling in 5 of the 6 cows inoculated. Lesions appeared on the

ends of all vaccinia virus inoculated teats, and progressed from a papule to a vesicle to a

scab. The SCC increased up to >500 000/ml, and vaccinia virus was isolated from the milk

of 4 out of 4 lactating cows up to 9 days pi (Easterday et al., 1959). Natural cases of bovine

mastitis, in which vaccinia virus was involved are unknown.

Outbreaks of cowpox virus are extremely rare. The virus enters through teat skin injuries

and several stages of lesion development can be observed. Erythematous areas appear on


the teat and can change into raised papule and ruptures with pitted centers. Lesions

spread rapidly throughout the herd. Healing occurs within 2–3 weeks although secondary

bacterial infections may delay resolution (Francis, 1984). During a cowpox virus

infection in India of cows and buffalo’s some animals suffered from mastitis (Sambyal

et al., 1983). Most of the affected cows showed teat lesions, and udder pathogens like

S. aureus and Klebsiella spp. were isolated from the milk of affected cows. The role of

cowpox virus in this case of mastitis was not clear, but the teat lesions, induced by

cowpox virus, might have resulted in secondary bacterial mastitis. The above mentioned

studies indicate that cowpox virus may play a role in bovine mastitis, but the incidence is

probably very low.

4.1.3. Pseudocowpox virus

The pseudocowpox virus belongs to the genus Parapoxvirus within the subfamily

Chordopoxvirinae of the Poxviridae family. Only one report was found concerning the

isolation of a poxvirus from milk (Dawson et al., 1968). The virus was isolated from a

pooled milk sample and typed as a virus from the paravaccinia subgroup, but no lesions

suggestive of pseudocowpox were recorded, neither was clinical nor subclinical mastitis.

An intramammary inoculation of one lactating cow with this strain did not result in

systemic disturbance, swelling or induration of the udder. Only a few small clots were

recorded in the milk on days 4 and 5 pi. No lesions developed on teats and on the udder. In

milk from 1 out of 2 inoculated quarters, the virus was isolated on only 24 h pi, but clinical

mastitis was not noted (Dawson et al., 1968). No further reports on pseudocowpox virus

and bovine mastitis were found, despite the fact that this virus is ubiquitous and the

infection induces comparable clinical signs as reported for BHV2 infections (Gibbs, 1984).

This suggests that, in addition to BHV2, pseudocowpox virus may also induce mastitis due

to damage of the mechanical defence mechanism of the udder. More data are required to

clarify the role and the impact of pseudocowpox virus infections in the aetiology of bovine

mastitis. The role of pseudocowpox virus in the aetiology of bovine mastitis is still an

interesting area for research; this virus was detected in 5 out of 14 cases of bovine teat

lesions in Dutch cattle (Wellenberg, 2001, unpublished data).

4.1.4. FMD virus

FMD virus can play a secondary role in bovine mastitis in that FMD virus infection may

result in ductus papillaris lesions and therefore enhances bacterial infections as reported for

an experimental Arcanobacter pyogenes udder infection (Saini et al., 1992). After an

infection of lactating cows with FMD virus, A. pyogenes had been isolated from 15 quarters

showing purulent mastitis (Saini et al., 1992), while an intramammary inoculation of

quarters with A. pyogenes alone did produce only mild inflammatory reactions (Vecht et al.,

1987). This suggests that the teat epithelium of the quarters had already been damaged by

FMD virus that supported the involvement of A. pyogenes as the causative agent of purulent

mastitis. The injury to teat epithelium was essential for the establishment of infection

(Seinhorst et al., 1991). Field studies also support a secondary role of FMD in bovine

mastitis. An increased incidence of bovine mastitis cases with secondary bacterial

pathogens has been reported after an infection with FMD virus (Ray et al., 1989; Seinhorst

et al., 1991).


4.1.5. Vesicular stomatitis virus

Mastitis has been associated with some other virus diseases, but it has not been

demonstrated that these viruses were the primary invaders of the mammary gland. Strozzi

and Ramos-Saco (1953) reported teat lesions and associated mastitis in cases of vesicular

stomatitis virus infections; a virus belonging to the genus Vesiculovirus within the

Rhabdoviridae family. An intramammary inoculation of eight cows with vesicular stomatitis

virus (New Jersey) did not induce udder swelling, but it resulted in increased milk SCC of

>500 000/ml in all five inoculated lactating cows. The virus was isolated from milk from

4 out of 5 lactating cows. In 5 out of 8 cows elevated body temperatures were recorded. No

changes were recorded in the bacterial flora of any quarter inoculated with vesicular

stomatitis virus during this study (Easterday et al., 1959). Although vesicular stomatitis

virus may play a role in bovine mastitis, the incidence is probably very low as the number of

reported mastitis cases in which vesicular stomatitis virus has been involved is nil.

4.1.6. Bovine papillomaviruses

The bovine papillomaviruses belong to the genus Papillomavirus within the family

Papillomaviridae. At least six types of bovine papillomavirus (BPV) have been recognised,

and certain types can cause fibropapillomas on teats (Olson, 1990). Fibropapillomas in the

ductus papillaris due to BPV may result in damage of the natural defence mechanisms of

the udder and therefore in a predisposition for mastitis (Francis, 1984). An ascending

bacterial infection may result in mastitis (William et al., 1992).

4.2. Immunosuppression

In addition to viruses that cause teat lesions, other viral infections may induce or enhance

bovine mastitis due to their immunosuppressive effects. Although, so far there is no any

clear evidence for this.

4.2.1. BHV1

BHV1 infections can impair the bovine immune system (Bielefeldt-Ohmann and

Babiuk, 1985; Straub, 1991; Nataraj et al., 1997; Saini et al., 1999; Koppers-Lalic

et al., 2001). Based on the immunosuppressive properties of BHV1, it has been proposed

that the virus may play a secondary role in the aetiology of diseases caused by bacteria

(Filion et al., 1983; Bielefeldt-Ohmann and Babiuk, 1985; Hutchings et al., 1990), but

whether and which secondary role BHV1 plays in the aetiology of bovine mastitis is not

clear. Epidemiological studies, to examine whether BHV1 seropositive animals are more

prone to bovine mastitis than BHV1 seronegative animals, are unknown. Hage et al. (1998)

reported a significant drop in milk production, which might be an indication for subclinical

mastitis, during a subclinical BHV1 infection on a dairy herd. However, no association was

found between the BHV1 infection and mastitis, since the milk SCC was unaltered and

clinical mastitis was not observed.

4.2.2. BVDV

Another virus that causes immunosuppression is BVDV, a member of the Pestivirus

genus, within the family of the Flaviviridae (Roth et al., 1981; Bolin et al., 1985; Markham


and Ramnaraine, 1985; Welsh et al., 1995). Persistently infected animals show chronically

impaired immunoresponses (Roth and Bolin, 1986; Brownlie, 1989), and a delay in the

onset of BRSV-specific IgG response and reduced antibody titres has been noted in cattle

infected concurrently with BVDV (Elvander, 1996). These data indicate that BVDV may

play an (indirect) role in the susceptibility of the animal to secondary infections, or may

enhance the possibility of secondary infections to run a more severe course (Potgieter et al.,

1984).

Studies on the immunosuppressive role of BVDV in relation to bovine mastitis are very

scarce. Siegler et al. (1984) reported an increased amount of mastitis cases in BVDV and

BHV1 seropositive herds, however, which role BVDV played in these mastitis cases in

unclear. Furthermore, a positive association between BVDV and bovine mastitis, based on

the BVDV antibody titers in bulk milk of 237 herds, has been reported. The number of

mastitis cases increased in herds with an increased BVDV antibody milk titer (Niskanen

et al., 1995). In a retrospective longitudinal study, which was conducted to examine

whether the exposure of dairy herds to BVDV affected udder health, a 7% increase was

noted in the incidence rate of clinical mastitis in herds exposed to BVDVas compared with

non-BVDVexposed herds (Waage, 2000). A reduction in the milk yield was shown in cows

that seroconverted for BVDV antibodies, although no information was presented on

mastitis (Moerman et al., 1994). Further studies are warranted to clarify the role of BVDV

in bovine mastitis. No intramammary inoculation of cows with BVDV has been reported,

and in addition there are no reports on the isolation of BVDV from milk of cows with

mastitis. However, BVDV genomic sequences can be detected by PCR in milk and bulk

milk samples (Radwan et al., 1995; Drew et al., 1999), but this is likely to be caused by the

presence of persistently infected cows in the herd, and consequently does not mean that the

virus is involved in a direct or indirect way in bovine mastitis cases.

4.2.3. BLV

An association of a virus infection with a higher susceptibility for bovine mastitis

has also been suggested for BLV. The primary target cells for BLV are cells of the

B-lymphocyte lineage in cattle. Infection of B-lymphocytes may influence the humoral

immune responses, e.g. a reduction in plasma IgM levels, and the cellular responses are

very probably as well impaired in BLV-infected cattle (Yamamoto et al., 1984; Meiron

et al., 1985). A possible association of BLV infections and mastitis in dairy cows has been

investigated on individual and on herd level, however, with contradictory results. A

positive association has been reported by Milojevic et al. (1991) and Rusov et al.

(1994), who reported that the occurrence of mastitis and increased cell counts are more

often recorded in cows with enzootic leukosis than in healthy cows. A significant

association between BLV seropositivity and higher milk SCC has also been recorded

for older cows (Jacobs et al., 1995), and Emanuelson et al. (1992) recorded a positive

association between BLV antibody positive bulk milk and bovine mastitis, and also for

bulk SCC.

However, a positive association has not been recorded in all studies performed. In a

matched case-control study, to assess the risk of clinical mastitis in BLV-infected cows,

the BLV-infected cows did not produce less milk, or did not develop mastitis more often

than did non-infected cows ðP > 0:05Þ (Huber et al., 1981). Also others reported that


BLV-infected cows had the same milk production, milk SCC and in addition the same

reproduction rate and mean age than non-infected cows (Langston et al., 1978; Scott et al.,

1991; Heald et al., 1992). No statistically significant association was found between BLV

infection and mastitis in 226 adult dairy cows examined for BLV infection and mastitis

(Fetrow and Ferrer, 1982). One of the reasons why results on studies on herd level are not in

agreement is that many studies did not use a proper study design. None of the studies

performed on individual or herd level clarify the role of BLV in the aetiology of bovine

mastitis.

4.2.4. Bovine immunodeficiency virus (BIV)

BIV, a lentivirus within the Retroviridae family, was detected for the first time in 1972.

Although most infections run a subclinical course, BIV infections may also result in

clinical signs such as lymphadenopathy, lymphocytosis, lesions of the central nervous

system, wasting and several secondary bacterial infections (Snider et al., 1996). Lymphoid

depletion with a reduction of the follicular development and depletion of B- and T-cell

compartments in lymph nodes are observed in BIV-infected animals. Secondary infections

were often multiple such as, e.g. metritis and mastitis (Snider et al., 1996). In this study, 24

(40%) out of 59 cows with a BIV infection showed chronic mastitis. Necrotising udder

tissue were recorded in combination with a few udder pathogens like E. coli. BIV

seropositivity was not associated with any changes in production (Jacobs et al., 1995).

The effect of co-infection with BLV and the influence of immunosuppression on the

severity of chronic bovine mastitis cases remains to be of interest for future investigations,

although it should be remarked that the impact of BIVon bovine mastitis is probably low as

BIV is not a major infectious agent for cattle and is of low or even not influence on major

economical losses.

5. Other viral infections, including non-bovine related virus infections,of the bovine mammary gland

A few other viral infections have been associated with bovine mastitis. For example,

mastitis, which may be secondary, has been attributed to a systemic virus disease such as

malignant catarrhal fever (Beckman et al., 1960). This report suggests that severe lesions in

the mammary gland may account for a decline in milk production and cracking of the

epithelium of the teats. However, this is the only report on any possible relation between

malignant catarrhal fever and mastitis.

5.1. Rinderpest virus

The role of rinderpest virus, a Morbillivirus and one of the members of the Paramyx-

oviridae family, in bovine mastitis has not been examined thoroughly. Infection of two

swamp buffaloes with a rinderpest virus, isolated from the spleen of an infected buffalo,

resulted in clinical signs as fever, depression and conjunctivitis, and vesicles appeared on

lips and mammary gland (Tesprateep et al., 1987). Natural primary or secondary cases of

mastitis due to rinderpest virus infections have not been reported.


5.2. Bovine enterovirus

Bovine enteroviruses are members of the genus Enterovirus in the Picornaviridae family.

This virus has been isolated from healthy cattle and cattle with enteric, respiratory and

reproductive disease problems (Knowles and Mann, 1990), but its role in mastitis is

unknown. After an intramammary inoculation of two cows with bovine enterovirus, an

acute catarrhal mastitis with marked increased milk SCC, and only mild clinical symptoms

were recorded in both cows. The virus was isolated from milk of inoculated quarters

(Straub and Kielwein, 1965).

5.3. Non-bovine related viruses

Also non-bovine related viruses have been shown to replicate in the bovine mammary

gland after intramammary inoculation (reviewed by Afshar and Bannister (1970)). An

inflammatory reaction in the bovine mammary gland was produced by infusion of the

Newcastle disease virus (strain Roakin). The intramammary inoculation of three cows, one

of which did not lactate, with Newcastle disease virus resulted in udder swelling and an

increase in body temperature in one of the inoculated cows. An increase in milk SCC was

recorded in the two inoculated lactating cows, and the milk also contained virus on day 6

after inoculation, but not on day 9 (Easterday et al., 1959). Mitchell et al. (1956) have

demonstrated that influenza and NCD viruses will multiply when inoculated into the

mammary gland (Mitchell et al., 1956). No mention was made of any inflammatory

processes. These studies show that non-bovine viruses are able to replicate in the bovine

mammary gland.

6. Concluding remarks

This review shows that viruses can be involved, in a direct or indirect way in the aetiology

of bovine mastitis. In natural cases of mastitis, BHV1, BHV4, FMD and PI3 viruses have

been isolated from milk. In addition, experimental infections via the ductus papillaris clearly

demonstrated that these viruses replicated in the mammary gland tissue, followed by clinical

mastitis in the cases of BHV1, FMD virus and PI3 virus infections, and subclinical mastitis

after a BHV4 infection. However, no investigations have been performed to examine

whether this route of infection is of importance in the field. Because bacterial pathogens

usually infect the udder through the ductus papillaris, it may be expected that also viruses

can infect the mammary gland tissue via this route after transmission by, e.g. milking

devices. Especially in cases when hygienic measures are not well taken. However, we

assume that BHV1, BHV4, FMD and PI3 viruses are mostly transmitted by direct contact

and by aerosols. That an experimental infection through the natural route leads to mastitis,

has been shown only for FMD (Table 1). However, in the Western world, FMD virus-

induced bovine mastitis is not of practical relevance because cattle infected with FMD virus

will be destroyed immediately after the diagnosis has been made. With regard to BHV1,

BHV4, PI3 virus and BLV infections, the data in the literature do not convincingly

demonstrate that these viruses can play a primary role in causing mastitis in the field.


It is likely that viruses that cause teat lesions (BHV2, cowpox, pseudocowpox, FMD,

vesicular stomatitis virus, and papillomaviruses), and thereby damaging the integrity of the

bovine udder, indirectly contribute to mastitis. The impact of these virus infections may be

great within individual herds but less within regions or districts of countries.

Although it is plausible that virus-induced immunosuppression underlies mastitis, there

are no data that underpin this assumption. In addition, only very few well-designed

epidemiological studies have been performed to support a causal relationship between

virus infections and mastitis.

Further research should be performed to firmly establish the importance of viral

infections on bovine mastitis in the field. Such research should certainly take into account

that mastitis is a multifactorial disease, consequently, such studies are difficult to design.

Investigations should deal with well-designed case-control studies, more experimental

viral infections whether or not in conjunction with bacterial infections, and various

epidemiological studies.

Application of new more powerful diagnostic tools, based on the detection of viral

genomic sequences. e.g. by (multiplex) PCR or micro-array devices, offer new opportu-

nities for a rapid simultaneous detection of most viruses involved in bovine mastitis. In the

future, these new screening methods may also provide a better insight in the prevalence of

viruses in milk from cows with mastitis.

Acknowledgements

We acknowledge J. van Dijk for making the initial steps for this review.

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Viral Infections and Bovine Mastitis - A Review

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